Document Type

Article

Publication Date

2-15-2025

Publication Title

Nat Commun

Keywords

JGM, Humans, RNA, Long Noncoding, Oligonucleotides, Antisense, Serine-Arginine Splicing Factors, Animals, Exons, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Mice, Xenograft Model Antitumor Assays, Nerve Tissue Proteins, Neoplasms, RNA Splicing

JAX Source

Nat Commun. 2025;16(1):1670.

Volume

16

Issue

1

First Page

1670

Last Page

1670

ISSN

2041-1723

PMID

39955311

DOI

https://doi.org/10.1038/s41467-025-56913-8

Grant

This work was supported by NIH grants R00CA178206, R01CA248317 and R01GM138541 to OA, and JAX Cancer Center pilot funds to OA (NCI P30CA034196). We acknowledge the use of shared resources supported by the JAX Cancer Center (NCI P30CA034196).

Abstract

Upregulated expression of the oncogenic splicing factor TRA2β occurs in human tumors partly through decreased inclusion of its autoregulatory non-coding poison exon (PE). Here, we reveal that low TRA2β-PE inclusion negatively impacts patient survival across several tumor types. We demonstrate the ability of splice-switching antisense oligonucleotides (ASOs) to promote TRA2β-PE inclusion and lower TRA2β protein levels in pre-clinical cancer models. TRA2β-PE-targeting ASOs induce anti-cancer phenotypes and widespread transcriptomic alterations with functional impact on RNA processing, mTOR, and p53 signaling pathways. Surprisingly, the effect of TRA2β-PE-targeting ASOs on cell viability are not phenocopied by TRA2β knockdown. Mechanistically, we find that the ASO functions by both decreasing TRA2β protein and inducing the expression of TRA2β-PE-containing transcripts that act as long non-coding RNAs to sequester nuclear proteins. Finally, TRA2β-PE-targeting ASOs are toxic to preclinical 3D organoid and in vivo patient-derived xenograft models. Together, we demonstrate that TRA2β-PE acts both as a regulator of protein expression and a long-noncoding RNA to control cancer cell growth. Drugging oncogenic splicing factors using PE-targeting ASOs is a promising therapeutic strategy.

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